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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal medullary endothelin B receptors contribute to blood pressure regulation by facilitating salt excretion. Premenopausal females have relatively less hypertension than males; therefore, we examined whether there is a sex difference in the natriuretic response to renal medullary infusion of endothelin peptides in the rat. All of the experiments were conducted in anesthetized wild-type (wt) or endothelin B-deficient (sl/sl) rats. Infusion of endothelin 1 (ET-1) significantly increased sodium excretion (U(Na)V) in female, but not male, wt rats (Delta U(Na)V: 0.41+/-0.07 versus -0.04+/-0.06 micromol/min, respectively). The endothelin B receptor agonist sarafotoxin 6c produced similar increases in U(Na)V in both male (Delta 0.58+/-0.15 micromol/min) and female (Delta 0.67+/-0.18 micromol/min) wt rats. Surprisingly, ET-1 markedly increased U(Na)V in female (Delta 0.70+/-0.11 micromol/min) but not male sl/sl rats (Delta 0.00+/-0.05 micromol/min). ET-1 had no effect on medullary blood flow in females, although medullary blood flow was significantly reduced to a similar extent in males of both strains. These results suggest that the lack of a natriuretic response to ET-1 in male rats is because of reductions in medullary blood flow. Treatment with ABT-627, an endothelin A receptor antagonist, or N(G)-propyl-L-arginine, an NO synthase 1 inhibitor, prevented the increase in U(Na)V observed in female rats. Gonadectomy eliminated the sex difference in the U(Na)V and medullary blood flow response to ET-1. These findings demonstrate that there is no sex difference in endothelin B-dependent natriuresis, and the endothelin A receptor contributes to ET-1-dependent natriuresis in female rats, an effect that requires NO synthase 1. These findings provide a possible mechanism for why premenopausal women are more resistant to salt-dependent hypertension.
Hypertension 2009 Feb
PMID:Contribution of endothelin A receptors in endothelin 1-dependent natriuresis in female rats. 1910 1

Leg ulcers may result in serious morbidity in patients with connective tissue diseases and Raynaud's phenomenon (RP). We describe a 35-year-old woman with mixed connective tissue disease who suffered from leg ulcers refractory to iloprost. When the patient was treated with the selective endothelin A receptor antagonist sitaxsentan for pulmonary arterial hypertension, the ulcers improved within 4 weeks and resolved completely thereafter. In addition, severity of RP ameliorated markedly. Further evaluation of sitaxsentan in patients with connective tissue diseases suffering from ischemic skin ulcers is required.
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PMID:[Leg ulcer in mixed connective tissue disease. Resolution during sitaxsentan therapy]. 1915 32

Ambrisentan is the second selective endothelin-A receptor antagonist to be licensed in Europe, and the first in the United States, for the management of pulmonary arterial hypertension (PAH). It has been shown to be clinically effective in improving exercise tolerance and functional class. Furthermore, ambrisentan is well tolerated and associated with low rates of liver toxicity and minimal interactions with other medicines commonly used to treat PAH. Overall, current data support a role for ambrisentan in the management of PAH. However, the results of longer-term follow-up studies are still required to fully assess efficacy and safety.
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PMID:Ambrisentan and its role in the management of pulmonary arterial hypertension. 1919 97

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT1 receptor antagonist losartan and the endothelin ETA receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague-Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by L-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT1 receptor blockade may be pivotal for long-term vascular and renal protection.
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PMID:Protective effects of angiotensin AT1 receptor blockade in malignant hypertension in the rat. 1932 69

Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.
Hypertension 2009 Jul
PMID:Blood pressure-independent reduction in proteinuria and arterial stiffness after acute endothelin-a receptor antagonism in chronic kidney disease. 1950 97

Endothelin is a potent vasoconstrictor substance that also can exert proliferative, inflammatory, and fibrotic changes in blood vessels and other organs. It acts on tissues in a paracrine and autocrine fashion, with local production and regulation occurring in both endothelial and nonendothelial cells. Endothelin stimulation of ETA and ETB receptors results in different and often opposing effects, which under physiologic conditions, establishes a balance that contributes to the regulation of vascular tone and blood pressure. Dysregulation of the endothelin system can induce or mediate endothelial dysfunction and organ damage in systemic hypertension (HTN), effects which may be ameliorated by endothelin antagonists. Endothelin receptor antagonists are currently being used in the treatment of pulmonary HTN. Both selective and dual-acting endothelin receptor blockers can also reduce systemic blood pressure in animal models and in hypertensive patients. Clinical trials evaluating the efficacy and safety of these agents are underway, and show potential as a new class of antihypertensives. Studies are also in progress with a single moiety dual angiotensin-endothelin A receptor antagonist, which is being evaluated in HTN. Issues that need to be addressed include the net contribution of endothelin in the pathophysiology of HTN, its interaction with other neurohormonal systems such as the renin-angiotensin-aldosterone system, and the clinical demonstration of the effect of endothelin receptor antagonism on end-organ damage in hypertensive patients.
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PMID:Endothelin as a clinical target in the treatment of systemic hypertension. 1952 80

Pulmonary hypertension (PH) is an important complication in the natural history of chronic obstructive pulmonary disease (COPD). Its presence is associated with reduced survival and greater use of healthcare resources. The prevalence of PH is high in patients with advanced COPD, whereas in milder forms it might not be present at rest but may develop during exercise. In COPD, PH is usually of moderate severity and progresses slowly, without altering right ventricular function in the majority of patients. Nevertheless, a small subgroup of patients (1-3%) may present with out-of-proportion PH, that is, with pulmonary arterial pressure largely exceeding the severity of airway impairment. These patients depict a clinical picture similar to more severe forms of PH and have higher mortality rates. PH in COPD is caused by the remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating agents (nitric oxide, prostacyclin) and increased expression of growth factors. Products contained in cigarette smoke play a critical role in the initiation of pulmonary endothelial cell alterations. Recognition of PH can be difficult because symptoms due to PH are not easy to differentiate from the clinical picture of COPD. Suspicion of PH should be high if clinical deterioration is not matched by the decline in pulmonary function, and in the presence of profound hypoxaemia or markedly reduced carbon monoxide diffusing capacity. Patients with suspected PH should be evaluated by Doppler echocardiography and, if confirmed, undergo right-heart catheterization in those circumstances where the result of the procedure can determine clinical management. To date, long-term oxygen therapy is the treatment of choice in COPD patients with PH and hypoxaemia because it slows or reverses its progression. Conventional vasodilators are not recommended because of their potential detrimental effects on gas exchange, produced by the inhibition of hypoxic pulmonary vasoconstriction and their lack of effectiveness after long-term treatment. In the subgroup of patients with out-of-proportion PH, new specific therapy available for pulmonary arterial hypertension (PAH) [prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors] may be considered in the setting of clinical trials. The use of specific PAH therapy in COPD patients with moderate PH is discouraged because of the potential detrimental effect of some of these drugs on gas exchange and there are no data demonstrating their efficacy.
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PMID:Pulmonary hypertension in patients with chronic obstructive pulmonary disease: advances in pathophysiology and management. 1953 34

Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome. Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra-arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by NG-monomethyl-L-arginine (NO synthase inhibitor; 4 micromol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (P<0.001), whereas infusion of NG-monomethyl-L-arginine induced smaller vasoconstriction in patients than in controls (P=0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (P=0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by NG-monomethyl-L-arginine (P=0.003) in patients but not in controls (both P>0.05). The favorable effect of ghrelin on endothelin A-dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (P=0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 microg/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans.
Hypertension 2009 Nov
PMID:Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity-related metabolic syndrome. 1978 44

Diabetes mellitus is a common disease and contributes to a high degree of morbidity and mortality. Cardiovascular complications, including diabetic cardiomyopathy are major causes of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy is a condition that affects the myocardium, primarily. It is not necessarily associated with ischemic heart disease, high blood pressure, valvular or congenital anomalies. The pathology of diabetic cardiomyopathy includes interstitial fibrosis, apoptosis of cardiomyocytes, abnormal energy utilization, small vessel disease and cardiac neuropathy. These pathologies are induced by hyperglycemia and oxidative stress. Biochemical as well as electrolyte changes, especially reduced calcium availability also occurs in the myocardium of diabetic patients. The abnormal structure and biochemistry of the myocardium result in functional problems such as diastolic and systolic dysfunctions, which may cause symptoms of dyspnea and inability to tolerate exercise. No single specific therapeutic agent can treat diabetic cardiomyopathy because once the disease is overt, the management may require a variety of approaches such as risk factors and lifestyle modification, glucose control (insulin, alpha glucosidase inhibitors, sulfonylureas, biguanides, meglitinides, thiazolidinediones and dipeptidyl peptidase 4 (DPP-4) inhibitors); hormones (IGF-1); ACE inhibitors (captopril, enalapril); angiotensin II receptor antagonists (losartan, olmesartan); beta adrenoreceptor antagonists (acebutolol, carvedilol); peptides (adrenomedullin); endothelin-1 receptor antagonists (bosentan, tezosentan); calcium channel blockers (amlodipine, verapamil); antioxidants (methalothionein, alpha tocopherol, alpha lipoic acid) and antihyperlipidemic drugs (simvastatin, fenofibrate, ezetimibe) to effectively treat patients with diabetic cardiomyopathy.
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PMID:Medicinal chemistry of drugs used in diabetic cardiomyopathy. 2001 35

Although soluble fms-like tyrosine kinase 1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor, has been implicated in the pathogenesis of hypertension during preeclampsia, the mechanisms whereby enhanced sFlt-1 production leads to hypertension remain unclear. Both sFlt-1 and endothelin 1 productions are elevated in women with preeclampsia and in placental ischemic animal models of preeclampsia; however, the importance of endothelin 1 and sFlt-1 interactions in the control of blood pressure during pregnancy is unknown. The purpose of this study was to determine the role of endothelin 1 in mediating sFlt-1-induced hypertension in pregnant rats. To achieve this goal, sFlt-1 (3.7 microg/kg per day for 6 days) was infused into normal pregnant rats and pregnant rats treated with a selective endothelin type A receptor antagonist, ABT 627 (5 mg/kg per day for 6 days). Plasma concentration of sFlt-1 increased from 735+/-34 pg/mL in normal pregnant rats to 2498+/-645 pg/mL (P<0.05) with infusion of sFlt-1. Arterial pressure increased from 100+/-1 mm Hg in normal pregnant rats to 122+/-3 mm Hg (P<0.05) in sFlt-1-infused rats. Chronic increases in plasma sFlt-1 in normal pregnant rats increased preproendothelin mRNA expression in the renal cortices by approximately 3-fold. In addition, chronic endothelin type A receptor blockade completely abolished the blood pressure response to sFlt-1 in pregnant rats (104+/-3 versus 100+/-1 mm Hg; P<0.05), whereas the endothelin A receptor antagonist had no effect on arterial pressure in NP rats (105+/-2 versus 100+/-1 mm Hg). In conclusion, this study demonstrates that endothelin 1, via endothelin type A receptor activation, plays an important role in mediating the hypertension in response to excess sFlt-1 during pregnancy.
Hypertension 2010 Feb
PMID:Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats. 2002 66


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